Treatment of Impulsive Aggression in Subjects With ADHD in Conjunction With Standard ADHD Treatment (CHIME 2)

Assessment of the Efficacy and Safety of Molindone Hydrochloride Extended-Release for the Treatment of Impulsive Aggression in Pediatric Patients With Attention Deficit/Hyperactivity Disorder in Conjunction With Standard ADHD Treatment

The purpose of this study is to demonstrate the efficacy, safety, and tolerability of SPN-810 in the treatment of impulsive aggression in patients with Attention-Deficit/Hyperactivity Disorder (ADHD) in conjunction with standard ADHD treatment. Approximately 297 subjects aged 6 to 12 years with ADHD and comorbid impulsive aggression will be recruited in this study. The frequency of impulsive aggression behaviors will be assessed as a primary outcome. Additionally, the severity and improvement in impulsive aggression and quality of life measures for the subject and caregiver will be assessed using validated scales.

Study Overview

• Status: Completed
• Conditions: Attention Deficit Hyperactivity Disorder (ADHD)
• Intervention / Treatment: Drug: SPN-810 (18 mg); Drug: SPN-810 (36 mg); Drug: Placebo

Detailed Description

This study is a randomized, placebo-controlled, double-blind, multicenter, parallel group, fixed dose study to demonstrate the efficacy, safety, and tolerability of SPN-810 in the treatment of IA in subjects aged 6 to 12 years with ADHD in conjunction with standard ADHD treatment.

• Study Type: Interventional
• Enrollment (Actual): 297
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Chandler, Arizona, United States, 85226
      • Metropolitan Neuro Behavioral Institute
  • Arkansas
    • Little Rock, Arkansas, United States, 72211
      • Woodland International Research Group
  • California
    • Imperial, California, United States, 92251
      • Sun Valley Research Center
    • Long Beach, California, United States, 90807
      • Alliance for Wellness dba Alliance for Research
    • Panorama City, California, United States, 91402
      • ASCLEPES Research Center
  • Colorado
    • Colorado Springs, Colorado, United States, 80910
      • MCB Clinical Research Centers, LLC
  • District of Columbia
    • Washington, District of Columbia, United States, 20310
      • Children's National Medical Center/Children's Research Institute
  • Florida
    • Fort Myers, Florida, United States, 33912
      • Gulfcoast Clinical Research Center
    • Hialeah, Florida, United States, 33012
      • Indago Research & Health Center, Inc.
    • Lauderhill, Florida, United States, 33319
      • Innovative Clinical Research, Inc
    • North Palm Beach, Florida, United States, 71103
      • Laszlo J. Mate, M.D., P.A.
    • Orlando, Florida, United States, 32803
      • APG Research, LLC
    • South Miami, Florida, United States, 33143
      • Miami Research Associates
    • Tampa, Florida, United States, 33613
      • University of South Florida- Dept. of Psychiatry and Neurosciences
  • Georgia
    • Atlanta, Georgia, United States, 30331
      • Atlanta Center for Medical Research
    • Decatur, Georgia, United States, 30030
      • iResearch Atlanta
  • Idaho
    • Meridian, Idaho, United States, 83642
      • Advanced Clinical Research
  • Illinois
    • Naperville, Illinois, United States, 60563
      • AMR Conventions Research
  • Indiana
    • Evansville, Indiana, United States, 47715
      • Pedia Research
  • Kentucky
    • Owensboro, Kentucky, United States, 42301
      • Pedia Research
  • Louisiana
    • Shreveport, Louisiana, United States, 71103
      • Louisiana State University Health Sciences Center
  • Missouri
    • Saint Charles, Missouri, United States, 63304
      • St. Charles Psychiatric Associates Midwest Research Center
  • Nebraska
    • Lincoln, Nebraska, United States, 68526
      • Alivation Research, LLC
    • Omaha, Nebraska, United States, 68114
      • Quality Clinical Research
  • New Jersey
    • Berlin, New Jersey, United States, 08009
      • Hassmann Research Institute
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Department of Psychiatry and Behavioral Neuroscience
  • Texas
    • Austin, Texas, United States, 78759
      • BioBehavioral Research of Austin P.C.
    • DeSoto, Texas, United States, 75115
      • InSite Clinical Research
    • Houston, Texas, United States
      • Houston Clinical Trials
  • Utah
    • Clinton, Utah, United States, 84015
      • Ericksen Research & Development
  • Washington
    • Bothell, Washington, United States, 98011
      • Pacific Institute of Medical Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 12 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Otherwise healthy male or female subjects, age 6 to 12 years at the time of screening with a primary diagnosis of ADHD and currently receiving monotherapy treatment with an optimized FDA-approved ADHD medication.
• Impulsive aggression will be confirmed at screening using R-MOAS and Vitiello Aggression Scale.

Exclusion Criteria:

• Current or lifetime diagnosis of epilepsy, major depressive disorder, bipolar disorder, schizophrenia or a related disorder, personality disorder, Tourette's disorder, or psychosis not otherwise specified.
• Currently meeting DSM criteria for autism spectrum disorder, pervasive developmental disorder, obsessive-compulsive disorder, post-traumatic stress disorder, or any other anxiety disorder as the primary diagnosis.
• Known or suspected intelligence quotient (IQ) < 70, suicidality, pregnancy, or substance or alcohol abuse.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Oral	Drug: Placebo; Subjects were randomized to receive Placebo twice each day with food, in the morning and in the evening, in addition to the stable dose of the optimized ADHD medication determined from the lead-in period. If initiating treatment before noon, patients should start with the morning dose; if afternoon, the evening dose.
Experimental: Low dose SPN-810 (18 mg); Oral	Drug: SPN-810 (18 mg); Subjects were randomized to receive SPN-810 9 mg twice each day with food, in addition to the stable dose of the optimized ADHD medication determined from the lead-in period. If initiating treatment before noon, patients should start with the morning dose; if afternoon, the evening dose.
Experimental: High dose SPN-810 (36 mg); Oral	Drug: SPN-810 (36 mg); Subjects were randomized to receive SPN-810 18 mg twice each day with food, in addition to the stable dose of the optimized ADHD medication determined from the lead-in period. If initiating treatment before noon, patients should start with the morning dose; if afternoon, the evening dose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy and Safety of SPN-810 on the Frequency of Impulsive Aggression (IA) Measured by the Impulsive Aggression Diary	The primary efficacy endpoint was percent change (PCHT) in the frequency (unweighted score) of IA behaviors per 7 days in the treatment (titration and maintenance) period relative to the Baseline period calculated over the number of days with non-missing IA diary data. PCHT was then calculated as 100 x (T - B)/B, where T and B are IA behavior frequencies per 7 days during the treatment period (from Day 2 through Visit 6, inclusive) and baseline period (Day ≤1), respectively. The IA behavior frequency per 7 days is defined as (SUM/DAY) x 7, where SUM is the total of the IA behaviors reported in the subject IA diary, and DAY is the number of days with a non-missing IA score in the subject IA diary during the specified study period.	Daily measure from Visit 2 (Week -2) to Visit 6 (Week 5) for a total of 7 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of SPN-810 on Impulsive Aggression Measured by Clinical Global Impression-Improvement (CGI-I) Scale Investigator Rated	The Clinical Global Impression - Improvement Scale (CGI-I) is an assessment of how much the patient's illness has improved or worsened relative to a baseline state at the beginning of treatment. CGI-I was evaluated by the Investigator at each visit on a 7-point scale with 1=very much improved, 2= much improved, 3= minimally improved, 4= no change, 5= minimally worse, 6= much worse, 7= very much worse	Visit 4 (Week 1), Visit 5 (Week 2) and Visit 6 (Week 5), a total of 4 weeks
Effect of SPN-810 on Impulsive Aggression Measured by Clinical Global Impression - Severity Scale (CGI-S)	The Clinical Global Impression - Severity of Illness (CGI-S) is a single item clinician rating of clinician's assessment of the severity of IA behaviors CGI-S was evaluated by the Investigator at each visit on a 7- point scale with 1=Normal, 2=Borderline ill, 3=Mildly ill, 4=Moderately ill, 5=Markedly ill, 6=Severely ill, and 7=Extremely ill. Data represent the change between Baseline (Visit 3/Day 1) and three time points: Visit 4 (Week 1); Visit 5 (Week 2) and Visit 6 (Week 5).	Baseline/Visit 3 (Day 1), Visit 4 (Week 1), Visit 5 (Week 2), and Visit 6 (Week 5). The total duration of the study was 5 weeks.
Effect of SPN-810 on Impulsive Aggression Measured by Child Health Questionnaire Parent Form 28-item (CHQ-PF28)	The CHQ-PF28 is a short generic measure of health status and health-related quality of life. The 28 items have 4, 5, or 6 response options, divided over 8 multi-item scales (physical functioning, general behavior, mental health, self-esteem, general health perceptions, parental impact: emotional, parental impact: time, and family activities) and 5 single item concepts (role functioning: emotional/behavior, role functioning: physical, bodily pain, family cohesion, and change in health). In addition, the individual scale scores will be aggregated to derive 2 summary component scores: the physical functioning and psychosocial health summary scores. The range on subscales and the overall scale is 0-100 (0 = worst possible health state; 100 = best possible health state). Data represent the change from Baseline (Visit 3) to one time point, Visit 6 (Week 5).	Baseline Visit 3 (Day 1) and Visit 6 (Week 5). Total duration of the study was 5 weeks.
Effect of SPN-810 on Impulsive Aggression Measured by Parenting Stress Index, Fourth Edition, Short Form (PSI-4-SF)	The PSI-4-SF is a 36-item self-report measure of parenting stress. Three subscales Parental Distress (PD), Parent-Child Dysfunctional Interaction (P-CDI), and Difficult Child (DC) consist of 12 items each. Parent chooses one of the 5 responses against each item. The 5 responses are: Strongly Agree (SA), Agree (A), Not Sure (NS), Disagree (D), and Strongly Disagree (SD) to indicate the degree to which they agree with each statement. The PD subscale raw score ranges from 12-60, P-CDI and DC each subscale raw score ranges from 16-56. The total stress raw score is the sum of the three subscales (PD+P-CDI+ DC) with a minimum score of 44 and a maximum score of 172. The total stress score is then converted into the percentile score. Parents with a 91st percentile or higher are experiencing clinically significant levels of stress. Data represents the mean change in percentile score from Baseline (Visit 3) and one time point, Visit 6 (Week 5).	Baseline Visit 3 (Day 1) and Visit 6 (Week 5). Total duration of the study was 5 weeks.
Effect of SPN-810 on Impulsive Aggression Measured by Clinical Global Impression-Improvement (CGI-I) Scale Caregiver Rated	The CGI scale was developed to provide a brief, stand-alone assessment of the clinician's view of a subjects' global functioning prior to and after administration of a study medication. The scale was also rated by the Caregiver to assess the improvement of IA behaviors. . CGI-I was evaluated by the Caregiver at each visit on a 7-point scale with 1=very much improved, 2= much improved, 3= minimally improved, 4= no change, 5= minimally worse, 6= much worse, 7= very much worse	Visit 4 (Week 1), Visit 5 (Week 2) and Visit 6 (Week 5), a total of 4 weeks
Effect of SPN-810 on Impulsive Aggression Measured by the Swanson, Nolan, Pelham Rating Scale- Revised (SNAP-IV) Rating Scale	The Swanson, Nolan, Pelham Rating Scale-Revised (SNAP-IV) includes 18 ADHD and 8 oppositional defiant disorder (ODD) symptoms. The symptoms are scored on a 4-point scale, not at all=0, just a little=1, Quite a bit= 2, very much=3. The ratings from the SNAP-IV scale are grouped into the following 4 subscales: ADHD Inattention (items #1-9), ADHD Hyperactivity/Impulsivity (items#10-18), ODD (items# 19-26), and ADHD-combined (first two scales combined, items #1-18). Each observed subscale score is the average rating of the items scores for the subscale where scores range from 0-3; the higher is the score, worsen is the outcome. Data represent the change of the observed scores between Baseline (Visit 3) and the end of the study, Visit 6 (Week 5).	Baseline Visit 3 (Day 1) and Visit 6 (Week 5). Total duration of the study was 5 weeks.
Effect of SPN-810 on Impulsive Aggression Measured by the Percentage of Responders	A Responder was defined as a subject with at least a 30% or 50% reduction in the frequency of IA behaviors per 7 days in the Treatment (Titration and Maintenance) period relative to the Baseline period per the IA Diary. Data represent the percentage of subjects with 30% and 50% reduction in IA behaviors from Baseline to end of treatment period.	Daily measure from Visit 2 (Week -2) to Visit 6 (Week 5) for a total of 7 weeks

Collaborators and Investigators

• Sponsor: Supernus Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): February 16, 2016
• Primary Completion (Actual): November 15, 2019
• Study Completion (Actual): February 14, 2020

Study Registration Dates

• First Submitted: November 20, 2015
• First Submitted That Met QC Criteria: November 25, 2015
• First Posted (Estimated): December 1, 2015

Study Record Updates

• Last Update Posted (Actual): March 18, 2024
• Last Update Submitted That Met QC Criteria: March 15, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Dyskinesias; Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders; Aberrant Motor Behavior in Dementia; Aggression; Attention Deficit Disorder with Hyperactivity; Hyperkinesis
• Other Study ID Numbers: 810P302